Why do some doctors prescribe cholesterol-reducing medication for which there is zero evidence of benefit?

In 2002 the Food and Drugs Administration (FDA) in the US licensed the cholesterol-lowering drug ezetimibe (Zetia). This medication reduces ‘unhealthy’ LDL-cholesterol levels by about 20 per cent. The assumption here is that this will reduce the risk of heart attacks and strokes. When ezetimibe was licensed, all of a sudden doctors had a new toy to play with and many rushed to prescribe it.

Then in 2008 came the release of results from the so-called ENHANCE study. This tested the effect of adding a ezetimibe to a statin on build-up of plaque on the inside of the body’s arteries, compared with taking a stain alone. The results of this study needed to be prised from its drug company sponsor, and no wonder: the results showed no benefit from the addition of ezetimibe and the additional cholesterol reduction it brought.

This, one might argue, would have sounded some sort of death knell for the drug in the ears of doctors. But a new study published in the American Heart Journal [1] suggests that this ‘bad news’ for ezetimibe was not precisely reflected in the prescribing practises of doctors.

For example, in Canada, it appears that prescriptions for ezetimibe increased steadily over from 2002 to 2009, with no let-up post-publication of the damning ENHANCE study. In the US, the situation was different, with prescription rates falling by about half after ENHANCE was published. However, rates of prescriptions in the US remained higher, overall, than in Canada.

We doctors like to believe ourselves to practice ‘evidence-based medicine’. But, in reality, we sometimes seem to have the capacity to ignore the evidence. There are plenty of reasons why this might be so, certainly one of which includes the fact that, historically, doctors have been encouraged to treat cholesterol levels down to a certain level. This means, in effect, that doctors have been encouraged to focus on cholesterol and their attention has been somewhat diverted from what is truly important (health outcomes). The fact is this: not one single study ever published has provided evidence that ezetimibe benefits health outcomes.

Late last year, the American College of Cardiology and the American Heart Association issued new guidelines on the management of cardiovascular disease. Here is one of the edicts from this set of guidelines:

Nonstatin therapies do not provide acceptable ASCVD [cardiovascular disease due to the clogging-up process known as ‘athersclerosis’] risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD.

If doctors act on this advice, then ezetimibe prescriptions should drop to precisely zero.

Should a doctor prescribe ezetimibe, then I don’t think it’s unreasonable for their patient to enquire about the evidence for this recommendation. This request may not get the best reaction, but I’d suggest that only through this sort of question may some doctors get to review their knowledge and practice, and offer truly evidence-based care.

References:

1. Lu L, et al. Impact of the ENHANCE Trial on the use of ezetimibe in the United States and Canada. Am H J published on-line 27 February 2014

Coincidence. I am 72 and feel pretty fit and active and am not overweight. I just returned from my doctor who wanted to put me on BP medication as my reading was slightly above the marker for my age,and also wanted to prescribe statins as my age and BP reading indicated that it would be a good idea. I declined statins and said that I would get more exercise and try other dietary interventions before I took BP medication. She looked at me as if I was crazy. I am a mature man but years of thinking that the medics are always right is difficult to resist.

The problem with studies is that the results apply to the average patient. I’m one of the outliers. Without drugs, my total cholesterol levels were over 400. I was in a clinical study of statins, and the maximum statin level did zilch for my LDL. The lipid expert said, “This is very strange.”

I felt it was because I was on a LC diet, eating fat and cholesterol, so I was getting plenty of cholesterol from my diet so my body didn’t need to synthesize it, and a drug that reduces its synthesis would have no effect. When ezetemide came out, we tried that, and it brought total cholesterol down to about 250. Then the statins worked to bring it down further.

Made perfect sense to me.

Whether or not high cholesterol is a risk factor for CVD is controversial. And there’s no evidence that statins help women. But “no evidence” doesn’t mean something is true. Before the DCTT people with diabetes were told there was no evidence that high blood glucose was harmful.

I think most people agree that *very high cholesterol* is not good. So if they remove ezetimide from the market, people like me will be in a difficult position.

Good point Gretchen. The argument of having more options available is always an important one, as in some cases a specific medication may provide benefit to just the right patient. I think the problem is that the data of increased use here suggests it’s not being used in this targeted fashion, but rather based on the previous assumption that added reduction of cholesterol is beneficial in general.

This happens with many drugs in which we find evidence that they are less effective than originally thought, as there is a lag time between reducing clinical use and evidence. Oddly, when the reverse occurs, and a drug is found the be beneficial in large studies, I don’t (subjectively) notice this same lag time.

This happened around 3 months ago. I was flipping through the TV channels when I stopped briefly onto a cable news show. The anchor hosting the show is a somewhat controversial figure in the US. A year earlier he had been found to plagiarize someone else’s work. As a result he received a slap on the wrist, and time off from work. It was the first time I had seen him back on TV.

So I’m watching, and the first segment to come up was an interview with a physician that specializes in cancer care. He had just written a new book. The interview was to discuss his writing and work as an oncologist. In introducing the author, the TV host really played up how the new book was entirely evidence based, everything had been carefully researched from top to bottom. Honestly, at the time I recall thinking I had not heard such an introduction before! Then the doctor is introduced and he begins mentioning that when it comes to cancer prevention he believes highly in 3 things. I forget the 3rd mention he made, but the first two beliefs where that taking statins were great at preventing cancer. Additionally taking aspirin was a big help too! Then he begins talking about a Greek physician from 2000 years ago and how he had found aspirin to be the mother of all health cures. Made me chuckle and roll my eyes. I wanted to yell out, next time you’re looking for story ideas don’t chose this guy! I did notice that the TV host made no challenges to the doctors evidence based science claims.

Thanks for highlighting this issue Dr. Briffa. It is also disturbing to see the citing of SEAS and SHARP which not only did not test ezetimibe monotherapy, but were interpreted in a positive light even though they were blatant failures.

John, We all have to make decisions on our own. It’s really a crap game. I wouldn’t urge you to take a statin if you don’t want to. I just printed out a study in PLOS claiming that statins reduce incidence of dementia in patients with type 2 diabetes. As I haven’t read it, I can’t comment on its validity.

My point was simply that the drug that benefits the most people may harm some, and vice versa.

I’m strongly of the opinion (and I can back this up) that statins prescribed for primary prevention are not warranted and their efficacy for secondary prevention is incidental with lifestyle changes / supplements being better advised.

The new bogeyman will soon be homocysteine but the best “therapy” is vitamin B / B12 so no profit for big pharma there then!

The study at the bottom of my comment shows that ezetimibe inhibits the transport of alpha tocopherol (vitamin E). Is that one of the reasons, Dr. Briffa, why ezetimide, though it lowers cholesterol, is not an effective drug against the bad consequences of high cholesterolemia? Vitamin E is well know to act on LDL oxidation and protect against atherosclerosis. Must we compulsorily add vitamin E when we take ezetimibe? Would it be effective?

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